What medications can cause elevated liver enzymes?

Medications That Can Cause Elevated Liver Enzymes

Numerous medications can cause elevated liver enzymes, with statins, antibiotics, anti-tuberculosis drugs, and immune checkpoint inhibitors being among the most common culprits. Understanding which medications pose risks and how to monitor for hepatotoxicity is essential for preventing serious liver injury.

Common Medication Classes Associated with Elevated Liver Enzymes

Cholesterol-Lowering Medications

• Statins: Can cause transaminase elevations in approximately 1% of patients 1
  • Simvastatin: Can cause persistent increases of hepatic transaminases >3× ULN 2
  • Atorvastatin: May cause liver enzyme elevations, particularly when used at higher doses 3
  • Risk increases with higher doses and when combined with other hepatotoxic drugs

Anti-Infective Agents

• Anti-tuberculosis drugs:

  • Isoniazid: Causes hepatitis; requires periodic ALT/AST monitoring, especially in first 3 months 1
  • Rifampin/Rifabutin: Can cause hepatitis; requires monitoring of liver enzymes 1
  • Ethambutol: Less hepatotoxic but still requires monitoring 1

• Macrolide antibiotics:

  • Clarithromycin and azithromycin: Can cause hepatitis; require periodic alkaline phosphatase, AST, and ALT monitoring for first 3 months 1

Immunomodulators and Biologics

• Immune checkpoint inhibitors: Can cause immune-mediated hepatitis 1

  • For Grade 2 (AST/ALT >3.0 to ≤5.0× ULN): Hold treatment and consider steroids 1
  • For Grade 3-4 (AST/ALT >5.0× ULN): Permanently discontinue treatment and start steroids 1

• Methotrexate: Requires liver biopsy monitoring at high cumulative doses; contraindicated in alcoholism and chronic liver disease 4

Antiviral Medications

• Lopinavir-ritonavir: ALT may increase to >5× ULN in 5% of patients 1
• Remdesivir: Can cause mild ALT elevation to >2× ULN 1
• Nevirapine: Associated with severe clinical hepatitis in up to 12% of female patients 4

Other Common Medications

• Montelukast and Zafirlukast: Zafirlukast has been associated with reversible hepatitis and rarely irreversible hepatic failure 1
• Zileuton: Can cause elevation of liver enzymes; limited reports of reversible hepatitis 1
• Niacin: Can cause hepatitis and elevations in liver enzymes 1
• Lomitapide: May cause elevations in liver transaminases; requires monitoring of ALT, AST, alkaline phosphatase, and total bilirubin 1

Monitoring Recommendations

General Monitoring Principles

1. Baseline testing: Obtain liver function tests before starting potentially hepatotoxic medications
2. Regular monitoring: Schedule varies by medication:
   • For statins: Monitor if symptoms develop 2, 3
   • For anti-TB drugs: Monitor every 1-3 months 1
   • For immune checkpoint inhibitors: Monitor before each infusion 1

When to Modify Treatment

• ALT/AST >3× ULN but ≤5× ULN: Consider dose reduction or temporary discontinuation with close monitoring 4
• ALT/AST >5× ULN: Discontinue medication and consider hepatology consultation 4
• Any elevation with symptoms: Immediately discontinue medication 4

Risk Factors for Medication-Induced Liver Injury

• Pre-existing liver disease
• Alcohol consumption
• Obesity
• Diabetes
• Advanced age
• Concomitant use of multiple hepatotoxic drugs
• Genetic factors affecting drug metabolism 4

Prevention Strategies

1. Avoid drug interactions: Be cautious with combinations of hepatotoxic medications

   • Example: Infliximab is contraindicated for immune-related hepatitis 1
   • Simvastatin with gemfibrozil, cyclosporine, or danazol is contraindicated 2

2. Dose adjustments: Consider lower doses in high-risk patients

   • For statins with interacting drugs: Switch to an alternate statin or adjust dose 2

3. Patient education:

   • Advise against alcohol consumption while taking hepatotoxic medications
   • Educate about avoiding over-the-counter medications containing acetaminophen
   • Instruct patients to report symptoms like fatigue, nausea, right upper abdominal discomfort, dark urine, or jaundice 2, 3

Special Considerations

• Patients with baseline elevated enzymes: Some medications (like statins) may still be used cautiously with more frequent monitoring 5
• Pregnancy: Many hepatotoxic medications are contraindicated in pregnancy 1
• Elderly patients: May require lower doses and more frequent monitoring due to decreased drug clearance

Remember that medication-induced liver injury can range from mild, asymptomatic elevations in liver enzymes to severe hepatotoxicity leading to liver failure. Early recognition and intervention are crucial to prevent serious outcomes.